 |
|
|
| |
Merck Sees No Dose-Response
Relationship With Doravirine, a New Nonnucleoside
|
| |
| |
16th International Workshop on Clinical Pharmacology of HIV and Hepatitis Therapy, May 26-28, 2015, Washington, DC
Mark Mascolini
Analysis of phase 2 trial data found no link between 48-week virologic response and levels of doravirine, an investigational nonnucleoside, regardless of viral load before treatment began [1]. On the basis of these findings and other considerations, a Merck team chose 100 mg once daily as the dose for phase 3 trials.
Doravirine, MK-1439, retains in vitro activity against HIV bearing either of two critical nonnucleoside mutations, K103N and Y181C, as well as against virus bearing both mutations. The phase 2 trial, however, compared doravirine with efavirenz (each with tenofovir/emtricitabine) in antiretroviral-naive people without nonnucleoside-resistant virus. In the first part of this trial, investigators randomized participants to 25, 50, or 200 mg of doravirine or to efavirenz. In part 2 all doravirine-treated patients switched to 100 mg and additional patients enrolled took either 100 mg of doravirine or standard-dose efavirenz [2]. After 48 weeks a noncompleter-equals-failure analysis figured sub-200-copy response rates of 83% in the combined doravirine arms (n = 166) and 79% in the efavirenz arm (n = 42). Respective sub-40-copy response rates were 76% and 71%.
For the dose-response analysis, Merck investigators combined sparsely collected pharmacokinetic (PK) data from 167 phase 2 participants with densely sampled data from a phase 1 study to yield individual post hoc estimates of steady-state PK values. The Merck team matched individual steady-state estimates with week-48 virologic results and explored pharmacokinetic/pharmacodynamic trends graphically. They also divided trough concentrations into equal-sized groups and plotted them against proportions of participants in each group with an undetectable viral load.
The analysis found no correlation between 48-week viral load and doravirine trough, maximum concentration, or 24-hour area under the concentration-time curve (AUC). The investigators found no difference in exposure-response trends between participants with a pretreatment viral load above 100,000 copies versus below 100,000 copies. Furthermore, the Merck team discerned no trends between doravirine PKs and proportions of participants with an undetectable 48-week viral load at doravirine doses ranging from 25 to 200 mg.
Finally, when the researchers plotted steady-state trough concentrations against baseline viral loads, the distribution of participants with versus without an undetectable viral load at week 48 suggested no trend between attaining an undetectable load and steady-state trough, regardless of pretreatment viral load.
"Overall," the Merck investigators concluded, "there is no evidence of an exposure-response relationship for . . . viral load or the proportion of [participants] achieving undetectable viral RNA at week 48." This finding, they proposed, "indicates attainment of a plateau over the dose range 25-200 mg once daily" in this phase 2 trial. Based on these findings and a risk-benefit assessment including potential drug interactions, activity against common nonnucleoside-resistant strains, and forgiveness of missed doses, Merck picked 100 mg once daily as the dose to test in phase 3 trials.
To support a planned phase 2 trial, Merck researchers also explored the effect switching from efavirenz to doravirine would have on doravirine concentrations [1]. They observed that taking doravirine with rifampin, a strong CYP3A4 inducer, cuts doravirine exposure. Thus they anticipated a transient drop in doravirine exposure when it follows efavirenz, a moderate CYP3A4 inducer.
To test that hypothesis they created a fixed-sequence design with three periods:
Period 1: 100 mg of doravirine once daily in the morning for 5 days followed by a 7-day washout
Period 2: 600 mg of efavirenz once daily at bedtime for 14 days
Period 3 (immediately following period 2): 100 mg of doravirine once daily in the morning for 14 days.
Comparing doravirine pharmacokinetics after efavirenz dosing with doravirine alone, the researchers confirmed a transient drop in doravirine exposure when the nonnucleoside starts immediately after efavirenz stops. For AUC the geometric mean for doravirine plus efavirenz versus doravirine alone rose from 0.38 a day after efavirenz stopped to 0.68 two weeks after efavirenz stopped. The doravirine trough concentration after efavirenz exceeded the 24-hour concentration target based on efficacy against wild-type virus (78 nM). One attendee argued that a sterner test would be the doravirine concentration target based on a single-mutant virus. Merck will analyze the clinical relevance of the transient interaction between doravirine and efavirenz in a phase 2 study of virologically suppressed patients switching from efavirenz to doravirine.
References
1. Yee K, Xu X, Teppler H. Doravirine efficacy exposure-response analysis at week 48 and implications. 16th International Workshop on Clinical Pharmacology of HIV and Hepatitis Therapy. May 26-28, 2015. Washington, DC. Abstract 5.
2. Gatell JM, Morales-Ramirez JO, Hagins DP, et al. Forty-eight-week efficacy and safety and early CNS tolerability of doravirine (MK-1439), a novel NNRTI, with TDF/FTC in ART-naive HIV-positive patients. J Int AIDS Soc. 2014;17(4 Suppl
3):19532. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4224904/
|
| |
|
|
|
|
|
